WO2024112391A1 - Compositions pour l'administration locale de principes actifs médicamenteux - Google Patents

Compositions pour l'administration locale de principes actifs médicamenteux Download PDF

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Publication number
WO2024112391A1
WO2024112391A1 PCT/US2023/035194 US2023035194W WO2024112391A1 WO 2024112391 A1 WO2024112391 A1 WO 2024112391A1 US 2023035194 W US2023035194 W US 2023035194W WO 2024112391 A1 WO2024112391 A1 WO 2024112391A1
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composition according
sitaxentan
sodium
composition
acid
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PCT/US2023/035194
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English (en)
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Zachary ROME
Keith Arthur Johnson
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Timber Pharmaceuticals, Inc.
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Publication of WO2024112391A1 publication Critical patent/WO2024112391A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • compositions for the local delivery of drug actives are particularly useful for the targeted dermal delivery of selective endothelin-A (ETA) receptor antagonists, such as for example sitaxentan.
  • ETA endothelin-A
  • These compositions are useful for treating, among other conditions, pigmentation disorders, cutaneous fibrosis, or connective tissue disorders, such as scleroderma and lichen sclerosus.
  • Topical or local delivery of drug actives can be important for providing targeted delivery to the skin or specific organs underlying the skin.
  • Topical delivery of a drug can provide an important alternative to systemic-based administration routes such as oral delivery or infusions or injections, particularly where it is desired to avoid overdosing of the drug and undesired side effects.
  • an objective of topical delivery is to maximize the concentration of the drug active to the target site, while minimizing systemic delivery to avoid the unnecessary delivery of the drug beyond the target site and to minimize or avoid unwanted side effects.
  • an objective of topical delivery is to provide improved thermodynamic delivery and pharmacokinetic and pharmacodynamic parameters often within a tight and focused therapeutic range.
  • ECM extracellular matrix components
  • Fibrosis can result in many different organs and tissues and there are several different types of fibrotic diseases, e.g., idiopathic pulmonary fibrosis, liver cirrhosis, scleroderma or systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis.
  • fibrotic diseases e.g., idiopathic pulmonary fibrosis, liver cirrhosis, scleroderma or systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis.
  • the effects of fibrosis and its complications can lead to significant morbidity, organ failure, and even death. See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693329/.
  • Some examples of drugs used in attempted treatment of scleroderma are calcium channel blockers, phosphodiesterase inhibitors, prostacyclin analogues, steroids, and immunosuppressants. These treatments, however, are often ineffective and/or have serious side effects. Additionally, people with scleroderma experience a significantly lower quality of life, and scleroderma places a considerable economic burden on health care systems and society. See https://www.ncbi.nlm.nih.gov/pubmed/28899803.
  • ET-1 stimulates cardiac contraction and the growth of cardiac myocytes, regulates the release of vasoactive substances (it is a potent vasoconstrictor), stimulates smooth muscle mitogenesis, and may control inflammatory responses by promoting the adhesion and migration of neutrophils and by stimulating the production of pro-inflammatory cytokines.
  • ET-1 has also been implicated in cancer progression, regulating the proliferation and migration of tumor cells and acting as a pro-angiogenic factor and inducer of stromal reaction. See https://www.ncbi.nlm.nih.gov/pubmed/27266371. Given the broad activity of endothelins, therapeutically controlling these peptides has been an area of interest for potential treatments for many different pathological conditions.
  • Bosentan a dual (i.e., a non-selective) ET-A/ET-B receptor antagonist, was developed for and is now FDA approved (in a tablet form) to treat pulmonary arterial hypertension (PAH). It is sometimes used “off-label” in the treatment armamentarium for scleroderma; however, it is often ineffective and associated with significant side effects. However, its effect is often modest, and its side effects limit utility. For example, bosentan has only been shown to help prevent the emergence of new digital ulcers in scleroderma and has no effect on the healing of existing ulcers. Liver enzyme abnormalities are a common side effect of treatment, affecting about 10% of patients and resulting in the cessation of treatment in about 5%.
  • the present invention relates to methods of use and local or topical compositions for the local or topical application of selective ET-A receptor antagonists or inhibitors for the treatment of cutaneous fibrosis or connective tissue disease.
  • the present invention relates to novel sitaxentan formulations, some of which are substantially free of ethanol. These compositions provide targeted dermal delivery system for the drug sitaxentan with minimal to no systemic penetration expected and improved thermodynamic activity using a gel formulation, and methods for treatment of cutaneous fibrosis or connective tissue disorders, such as lichen sclerosus and scleroderma.
  • the present invention is based on the surprising discovery that sitaxentan, a highly selective ET-A receptor antagonist, was significantly more effective than both a vehicle control and than bosentan, a non-selective ET-A/ET-B receptor antagonist, at reducing collagen production, reducing viability, inducing apoptosis, and reducing fibroblast migration in human dermal fibroblasts induced with transforming growth factor beta 1 (TGF-01 ) to stimulate a pro-fibrotic phenotype.
  • TGF-01 transforming growth factor beta 1
  • compositions for local administration may have a selective endothelin-A receptor antagonist or a pharmaceutically acceptable salt, ester, prodrug, polymorph, or solvate thereof.
  • the composition may optionally be substantially free of ethanol.
  • the selective endothelin-A (ET-A) receptor antagonist or inhibitor may have a selectivity of at least ten-fold over endothelin-B (ET-B).
  • the selective endothelin-A (ET-A) receptor antagonist or inhibitor may have a selectivity of at least 100-fold over endothelin-B (ET-B).
  • the selective endothelin-A (ET-A) receptor antagonist or inhibitor may have a selectivity of at least 5000-fold over endothelin-B (ET-B).
  • the pharmaceutically acceptable salt may be selected from an alkali metal salt, an alkaline earth metal salt, and an ammonium salt.
  • the alkali metal salt may be selected from lithium, sodium, and potassium.
  • the alkali metal salt may be sodium.
  • the pharmaceutically acceptable salt may be sitaxentan sodium.
  • the composition may demonstrate at least one of the following pharmacokinetic parameters selected from a Cmax less than about 13 pg/ml, or a Cmax less than about 7 pg/ml, or an AUC less than about 40 pg hr/ml.
  • the composition may comprise from about 0.1 % (w/w) to about 10% (w/w) of sitaxentan sodium.
  • the composition may comprise from about 0.5% (w/w) to about 5% (w/w) of sitaxentan sodium. In another aspect, the composition may comprise from about 1 % (w/w) to about 2% (w/w) of sitaxentan sodium.
  • composition may comprise from about 1 % (w/w) sitaxentan sodium.
  • the composition may be selected from the group consisting of (i) a water-containing composition or (ii) a composition that is substantially free of water.
  • the composition may be a water-containing composition.
  • the composition may comprise: (a) a humectant, (b) glycerol, (c) an antioxidant, and (d) a chelating agent.
  • the humectant may be selected from the group consisting of a C3-C6 polyol, wherein the C3-C6 polyol is other than glycerol.
  • the C3-C6 polyol may be selected from the group consisting of 1 ,2-propylene glycol, 1 ,3 propylene glycol, 1 ,2-butylene glycol, 1 ,4-butylene glycol, 1 ,2- hexylene glycol, mannitol, sorbitol, xylitol, and combinations thereof.
  • the C3-C6 polyol may have at least hydroxy groups on adjacent carbon atoms.
  • the C3-C6 polyol may be propylene glycol.
  • the antioxidant may be selected from the group consisting of acetone sodium bisulfite, alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid monohydrate, dodecyl gallate, erythorbic acid, fumaric acid, malic acid, mannitol, sorbitol, monothioglycerol, octyl gallate, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, thymol, vitamin E polyethylene glycol succinate, and N- acetylcysteine, or a combination thereof, and combinations thereof.
  • the antioxidant may be ascorbic acid.
  • the chelating agent may be selected from ethylenediaminetetraacetic acid (EDTA), citric acid, tartaric acid, triethanolamine, and combinations thereof.
  • EDTA ethylenediaminetetraacetic acid
  • citric acid citric acid
  • tartaric acid tartaric acid
  • triethanolamine triethanolamine
  • the chelating agent may be ethylenediaminetetraacetic acid (EDTA).
  • the composition may be in the form of a gel further comprising (e) an N-vinylpyrrolidone polymer.
  • the N-vinylpyrrolidone polymer may be a homopolymer.
  • the N-vinylpyrrolidone homopolymer may have a k value from about 15 to about 90.
  • the N-vinylpyrrolidone homopolymer may have a k value of about 30 to 60.
  • the N-vinylpyrrolidone homopolymer may be Povidone K30.
  • the composition may have a viscosity of about 1000 to about 10,000 cP at 20° C (Brookfield LV viscometer, 13R sample holder, Spindle 21 , 0.3 rpm).
  • the composition may have a viscosity of about 2,000 to 6,000 cP at 20° C (Brookfield LV viscometer, 13R sample holder, Spindle 21 , 0.3 rpm).
  • the composition may be substantially free of water.
  • composition may be in the form of an ointment.
  • composition may further comprise: (a) a hydrocarbonbased oil, semisolid, or wax; (b) a surfactant or a combination of surfactants; and (c) an antioxidant or a combination of antioxidants.
  • hydrocarbon-based oil, semisolid or wax may be selected from the group consisting of mineral oil, paraffin, petrolatum, and combinations thereof.
  • the surfactant may be selected from the group consisting of sorbitan sesquioleate, glyceryl monostearate, and combinations thereof.
  • the antioxidant may be selected from the group consisting of acetone sodium bisulfite, alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid monohydrate, dodecyl gallate, erythorbic acid, fumaric acid, malic acid, mannitol, sorbitol, monothioglycerol, octyl gallate, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, thymol, vitamin E polyethylene glycol succinate, and N- acetylcysteine, or a combination thereof, and combinations thereof.
  • the antioxidant may be selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, and combinations thereof.
  • a semi-solid composition for local administration may comprise: (a) from about 0.1 % (w/w) to about 5% (w/w) of sitaxentan sodium, (b) from about 5% (w/w) to about 25% (w/w) of propylene glycol, (c) from about 50% (w/w) to about 80% (w/w) of glycerol, (d) from about 5% (w/w) to about 25% (w/w) of Povidone K30, (e) from about 0.01 % (w/w) to about 0.5% (w/w) of ascorbic acid, (f) from about 0.001 % (w/w) to about 0.1 % (w/w) of ethylene diamine tetraacetic acid, and (g) from about 1 %
  • a semi-solid composition for local administration may comprise: (a) about 1 % (w/w) of sitaxentan sodium, (b) about 14.89% ( ⁇ 15% or Q.S. (w/w) of propylene glycol,
  • a semi-solid composition for local administration may comprise: (a) from about 0.1 % (w/w) to about 5% (w/w) of sitaxentan sodium, (b) from about 5% (w/w) to about 25% (w/w) of propylene glycol, (c) from about 50% (w/w) to about 80% (w/w) of glycerol,
  • an ointment composition for local administration may comprise: (a) from about 0.1 % (w/w) to about 5% (w/w) of sitaxentan sodium, (b) from about 10% (w/w) to about 20% (w/w) of mineral oil, (c) from about 1 % (w/w) to about 10% (w/w) of paraffin, (d) Q.S.
  • a method for treating cutaneous fibrosis or a connective tissue disease is disclosed.
  • the method may comprise locally or topically applying a therapeutically effective amount of a composition according to any of the foregoing compositions, to a mammal in need thereof.
  • the mammal may be a human patient.
  • the cutaneous fibrosis or connective tissue disorder may be selected from scleroderma, systemic sclerosis, localized scleroderma, diffuse systemic sclerosis, limited systemic sclerosis, Raynaud’s phenomenon, Peyronie’s disease, sclerodactyly, cutaneous ulcers, morphea, en coup de sabre, cicatricial alopecia, scarring alopecia, lichen planopilaris, lichen planus, lichen sclerosus, lichen sclerosus et atrophicus, frontal fibrosing alopecia, central centrifugal cicatricial alopecia, folliculitis decalvans, discoid lupus erythematous, dissecting cellulitis, rheumatoid arthritis, lupus, lichen sclerosus, keloid scars, hypertrophic scars, burn scars, and combinations thereof.
  • the cutaneous fibrosis or connective tissue disorder may be scleroderma.
  • the cutaneous fibrosis may be lichen sclerosus.
  • the selective endothelin-A (ET-A) receptor antagonist or inhibitor composition may be applied at least one daily, or at least twice daily, or at least three times per day, or at least four times per day, or is applied as needed (ad libitum).
  • the use of a selective endothelin-A (ET- A) receptor antagonist or inhibitor in the manufacture of a medicament for local or topical delivery of a therapeutically effective amount of the selective endothelin-A (ET-A) receptor antagonist or inhibitor for treating cutaneous fibrosis or a connective tissue disease in a mammal in need thereof is disclosed.
  • the medicament may comprise a composition according to any of the foregoing compositions.
  • FIG. 1 shows scratch assay experimental results for male normal human dermal fibroblasts (NHDFs) that were exposed to 50 ng/mL of transforming growth factor- (31 (TGF-pi ) for 24 hours, prior to treatments comparing sitaxentan (SIT, 100 pM), against bosentan (BOS, 100 pM as a comparator compound) and vehicle control (VC).
  • NHDFs male normal human dermal fibroblasts
  • TGF-pi transforming growth factor-
  • BOS bosentan
  • VC vehicle control
  • FIG. 2 shows scratch assay experimental results for female normal human dermal fibroblasts (NHDFs) that were exposed to 50 ng/mL transforming growth factor- pi (TGF- i ) for 48 hours, prior to treatments comparing sitaxentan (SIT, 100 pM), against bosentan (BOS, 100 pM as a comparator compound) and vehicle control (VC).
  • NHDFs female normal human dermal fibroblasts
  • TGF- i transforming growth factor- pi
  • VC vehicle control
  • HSD transforming growth factor-pi
  • SIT sitaxentan
  • BOS bosentan
  • RFUs relative fluorescence units
  • SIT sitaxentan
  • BOS bosentan
  • RFUs relative fluorescence units
  • FIG. 6 shows experimental results for male normal human dermal fibroblasts (NHDFs) which were stimulated with 50 ng/mL transforming growth factor- (31 (TGF-[31 ) for 48 hours.
  • Apoptosis was measured comparing sitaxentan (SIT, 100 pM), against bosentan (BOS, 100 pM as a comparator compound) and vehicle control (VC), and reported as relative light units (RLUs) on the y-axis.
  • SIT sitaxentan
  • BOS bosentan
  • VC vehicle control
  • RLUs relative light units
  • FIG. 7 shows a plot of transepithelial delivery of sitaxentan from various compositions.
  • FIG. 8 shows a plot of the percent delivery of sitaxentan from various compositions.
  • FIG. 9 shows a plot of the amount of sitaxentan in the dermis from various compositions.
  • FIG. 10 shows a plot of the amount of sitaxentan in the epidermis from various compositions.
  • the present invention provides semi-solid compositions for the topical delivery of sitaxentan, or a pharmaceutically acceptable salt thereof, for treating cutaneous fibrosis or connective tissue disorders, such as scleroderma.
  • the term "dermal" administration means transport of an agent across the stratum corneum and into the dermis and/or epidermis for treatment of cutaneous fibrosis or connective tissue disorders, such as lichen sclerosus and scleroderma, that responds to local, non-systemic administration of an agent. It will be appreciated that some of the active agent intended for dermal therapy can be transdermally administered, however typically not in an amount sufficient for therapy.
  • the term “local” as used herein with respect to pharmaceutical compositions means a route of administration of a composition in which the pharmacodynamic effect is generally contained around the application location and does not result in significant or rapid concentrations in the blood or other tissues.
  • permeation rate means the rate of passage of the drug through the skin. Permeation rate is calculated as the slope of the linear portion of the cumulative amount of drug permeated per cm 2 over time.
  • compositions in other words the formulations, of the present invention, and also with respect to sitaxentan and the salts of sitaxentan, i.e. , the pharmaceutically acceptable salts.
  • the pharmaceutical compositions of the present invention comprise a therapeutically effective amount of sitaxentan and a pharmaceutically acceptable carrier. These carriers can contain a wide range of excipients.
  • Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles.
  • the compositions are made using common formulation techniques. See, for example, Remington’s Pharmaceutical Sciences, 17 th edition, edited by Alfonso R. Gennaro, Mack Publishing Company, Easton, PA, 17th edition, 1985. Regarding pharmaceutically acceptable salts, these are described below.
  • the term “selective” with respect to ET-A antagonist or inhibitor means an ET-A inhibitor which preferentially inhibits ET-A versus ET-B.
  • the selectively for ET-A versus ET-B should be at least two-fold, preferably at least five-fold, more preferably at least ten-fold, more preferably at least 100-fold, more preferably at least 1000-fold, and most preferably at least 5000-fold.
  • selectivity can be important for providing the therapeutic benefits of the present invention.
  • a rationale for this selectively, compared to that for a non-selective inhibitor such as bosentan is the negligible inhibition of the beneficial effects of ET-B stimulation, such as nitric oxide production and clearance of endothelin from circulation.
  • the terms “semi-solid” and “gel” refer to the characteristics of the compositions of the present invention.
  • Semi-solid refers to a highly viscous material.
  • Gel refers to a thick, clear, slightly sticky substance, especially one used in cosmetic or medicinal products.
  • the compositions of the present invention have a viscosity of about 100 cP to about 25,000 cP, or 1000 cP to about 10,000 CP, or about 2500 cP to about 5000 cP, or about 4000 cP at 20° C, as measured using an LV viscometer, 13R sample holder, Spindle 21 , at 0.3 rpm.
  • the term “subject” means a human patient or animal in need of treatment or intervention for cutaneous fibrosis or connective tissue disorders.
  • water-containing composition means that the composition is contemplated to comprise water as a formulation component.
  • a composition that contains water may comprise an amount of water that is greater than or equal to about 10% (w/w), or 15% (w/w), or 20% (w/w), or 30% (w/w), or 40% (w/w), or 50% (w/w), or 60% (w/w), or 70% (w/w), or 80% (w/w).
  • a skilled formulator will be able to determine a suitable amount of water based on the other components of the composition.
  • the term substantially free of water means that the compositions, such as the ointments contain no appreciable or noticeable amount of water. These compositions contain less than about 1 %(w/w) of water, or less that about 0.5% (w/w) of water, or less than about 0.25% (w/w) of water, or less than about 0.10% (w/w) of water, or less than about 0.05% (w/w) of water, or less than about 0.01 % (w/w) of water. Although no specific lower level of water is specifically contemplated for these compositions, it should be understood by one of ordinary skill in the formulation arts that these compositions should contain as close to 0% (w/w) of water as is practical. Alternatively, these compositions can also be described as anhydrous compositions.
  • the term optionally substantially free of ethanol means the compositions optionally contain no appreciable or noticeable amount of ethanol. These compositions optionally contain less than about 1 %(w/w) of ethanol, or less that about 0.5% (w/w) of ethanol, or less than about 0.25% (w/w) of ethanol, or less than about 0.10% (w/w) of ethanol, or less than about 0.05% (w/w) of ethanol, or less than about 0.01 % (w/w) of ethanol. Although no specific lower level of ethanol is specifically contemplated it should be understood by one of ordinary skill in the formulation arts that the compositions should contain as close to 0% (w/w) of ethanol as is practical.
  • the term “therapeutically effective” means an amount of sitaxentan needed to provide a meaningful or demonstrable benefit, as understood by medical practitioners, to a subject, such as a human patient or animal, in need of treatment.
  • the term is intended to encompass an amount of sitaxentan sufficient to prevent or reduce the symptoms associated with a disease or condition and/or lessen the severity of the disease or condition.
  • a therapeutically effective amount is understood to be in context to the condition being treated, where the actual effective amount is readily discerned by those of skill in the art.
  • Conditions, intended to be treated include, for example, cutaneous fibrosis and connective tissue disease, such as scleroderma.
  • a meaningful or demonstrable benefit can be assessed or quantified using various clinical parameters.
  • the demonstration of a benefit also includes those provided by models, including but not limited to in vitro models, in vivo models, and animal models.
  • An example of such a model is the Human Procollagen Type I C-peptide (PIP) assay. This model is designed to detect and quantify human procollagen in human serum, plasma, cell culture supernatants, cell lysate, and tissue homogenates in a variety of experimental states via AlphaLISA® technology.
  • An example of an animal model which can be employed is the bleomycin induced skin fibrosis model. See, https://www.ncbi.nlm.nih.gov/pubmed/24706279.
  • topical as used herein with respect to pharmaceutical compositions means a composition that is applied to the skin or mucosal membrane of a subject, such as a human patient.
  • a topical pharmaceutical composition is intended to have an effect at the site of application, i.e., in the tissue beneath the site of application, and does not result in significant drug concentrations in the blood and other tissues.
  • Topical pharmaceutical compositions are in contrast to “transdermal” or “transmucosal” pharmaceutical compositions, which are absorbed through the skin or mucosal membranes and are intended to have a systemic effect in areas of the body away from the site of application. See, http://corporatepharmacy.ca/health- news/topical-vs-transdermal-meds, (2016).
  • transdermal means administration through the dermal layer of the skin to the systemic circulation by diffusion.
  • the term "transport rate” refers to the rate of passive drug transport across human skin as governed by Fick's Law of diffusion.
  • the mass transport equation is given as: J - 1/A(dM/dt) - P.DELTA.C dt where J is flux (mu.g cm 2 /hr), A is cross sectional area of the skin membrane (cm.sup.2), P is the apparent permeability coefficient (cm hr), .DELTA.C is the concentration gradient across the membrane, and (dM/dt) is the mass transport rate.
  • the terms “treat,” “treating” or “treatment,” include alleviating, abating or ameliorating the condition, e.g. cutaneous fibrosis or connective tissue disorders, such as scleroderma, or preventing or reducing the risk of contracting the condition or exhibiting the symptoms of the condition, ameliorating or preventing the underlying causes of the symptoms, inhibiting the condition, arresting the development of the condition, relieving the condition, causing regression of the condition, or stopping the symptoms of the condition, either prophylactically and/or therapeutically.
  • condition e.g. cutaneous fibrosis or connective tissue disorders, such as scleroderma
  • ameliorating or preventing the underlying causes of the symptoms inhibiting the condition, arresting the development of the condition, relieving the condition, causing regression of the condition, or stopping the symptoms of the condition, either prophylactically and/or therapeutically.
  • preventing, prophylaxis, or reducing the risk of are intended to refer to the administration of the sitaxentan active to stop or prevent the condition or disease from occurring in the first place or to reduce the probability of the disease from occurring and are intended to be included with and/or as alternatives to “treat”, “treating”, or “treatment”.
  • the methods of treatment using sitaxentan or a pharmaceutically acceptable salt thereof or the pharmaceutical compositions of the present invention also include the use of sitaxentan or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the desired treatment, such as cutaneous fibrosis and connective tissue diseases, such as scleroderma.
  • ET-A is an abbreviation for endothelin-A.
  • ET-B is an abbreviation for endothelin-B.
  • TGF-[31” is an abbreviation for transforming growth factor- [31 .
  • NHDF is an abbreviation for normal human dermal fibroblasts.
  • the present invention utilizes a therapeutically effective amount of a selective endothelin-A (ET-A) receptor antagonist or inhibitor such as sitaxentan or a pharmaceutically acceptable salt thereof, and also a pharmaceutically acceptable carrier for providing local or topical compositions for treating conditions such as cutaneous fibrosis and connective tissue disorders.
  • a selective endothelin-A (ET-A) receptor antagonist or inhibitor such as sitaxentan or a pharmaceutically acceptable salt thereof
  • a pharmaceutically acceptable carrier for providing local or topical compositions for treating conditions such as cutaneous fibrosis and connective tissue disorders.
  • Sitaxentan also known as sitaxsentan, corresponds to the CAS Registry Number 184036-34-8 and the IIIPAC name N-(4-Chloro-3-methyl-5-isoxazolyi)-2-[(2-methyl-4,5- methylenedioxyphenyl)- acetyl]thiophene-3-sulfonamide, and also the code name TBC- 11251 .
  • Sitaxentan sodium salt the form of the drug developed for human use, has the CAS Registry Numbers 210421-64-0 and 210421 -74-2.
  • Sitaxentan was developed as an oral tablet for the treatment of pulmonary arterial hypertension (PAH) and was marketed as Thelin® by Encysive Pharmaceuticals until purchased by Pfizer in February 2008.
  • Sitaxentan has the chemical formula C18H15CIN2O2S2 and a molar mass of 454.906 g/mol. The following pharmacokinetic data is reported:
  • Metabolism hepatic (CYP2C9- and CYP3A4-mediated)
  • Sitaxentan is described as a small molecule that blocks or inhibits the action of endothelin (ET) on the endothelin-A (ET-A) receptor selectively. This selectivity is reported to be by a factor of 6000 compared to endothelin-B- (ET-B). See, Girgis, RE; Frost, AE; Hill, NS; Horn, EM; Langleben, D; McLaughlin, VV; Oudiz, RJ; Robbins, IM; et al. (2007). "Selective endothelin-A receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease”. Annals of the rheumatic diseases. 66 (11 ): 1467-72. doi:10.1136/ard.2007.069609. PMC 2111639 Freely accessible. PM D 17472992. Such selectivity can be important for providing the therapeutic benefits of the present invention.
  • compositions of the present invention are useful for the methods and compositions of the present invention.
  • pharmaceutically acceptable salts refer to derivatives of sitaxentan modified by making salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, alkali metal salts, alkaline earth metal salts, and ammonium salts.
  • alkali metal salts include lithium, sodium, and potassium salts.
  • alkaline earth metal salts include calcium and magnesium salts.
  • the ammonium salt, NH4 + . itself can be prepared, as well as various monoalkyl, dialkyl, trialkyl, and tetraalkyl ammonium salts.
  • one or more of the alkyl groups of such ammonium salts can be further substituted with groups such as hydroxy groups, to provide an ammonium salt of an alkanol amine.
  • Ammonium salts derived from diamines such as 1 ,2-diaminoethane are contemplated herein.
  • the sodium salt of sitaxentan, also called sitaxentan sodium, is useful herein. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).
  • the pharmaceutically acceptable salts of sitaxentan can be prepared from the parent compound by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of the appropriate base in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • metabolites of sitaxentan which can be administered directly or generated in vivo from the administration of the sitaxentan.
  • the present invention comprises a therapeutically effective amount of sitaxentan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Compositions based on a unit dosage can comprise, from about 0.1 mg to about 1000 mg of sitaxentan or a pharmaceutically acceptable salt thereof, based on the weight of the sitaxentan active.
  • Examples of other dosages are 1 mg, 10 mg, 50, mg, 100 mg, and 500 mg of sitaxentan or a pharmaceutically acceptable salt thereof, based on the weight of the sitaxentan active.
  • compositions can also be prepared based on weight percentages.
  • compositions useful here comprise from about 0.001 % to about 25% by weight (w/w) sitaxentan or a pharmaceutically salt thereof, based on the weight of the sitaxentan active.
  • compositions useful here comprise from about 0.01 % to about 10% by weight sitaxentan or a pharmaceutically salt thereof, based on the weight of the sitaxentan active.
  • compositions useful here comprise from about 0.1 % to about 5% by weight sitaxentan or a pharmaceutically salt thereof, based on the weight of the sitaxentan active.
  • compositions useful here comprise from about 0.2% to about 3% by weight sitaxentan or a pharmaceutically salt thereof, based on the weight of the sitaxentan active.
  • compositions useful here comprise from about 0.5% to about 2% by weight sitaxentan or a pharmaceutically salt thereof, based on the weight of the sitaxentan active.
  • compositions useful here comprise from about 0.75% to about 1 .5% by weight sitaxentan or a pharmaceutically salt thereof, based on the weight of the sitaxentan active. In one embodiment the compositions useful here comprise from about 0.9% to about 1.1 % by weight sitaxentan or a pharmaceutically salt thereof, based on the weight of the sitaxentan active.
  • compositions useful here comprise about 1 % by weight sitaxentan or a pharmaceutically salt thereof, based on the weight of the sitaxentan active.
  • the amount or weight percentage of the sitaxentan is determined or calculated based on the actual amount of the sitaxentan moiety, which has a molar mass of 454.906, and not including the additional weight provided by any counter ions when a sitaxentan salt is used. In other words, the compositions are based on the amount or weight percentage of the sitaxentan chemical moiety.
  • the unit dosage could be formulated to demonstrate at least one of the following pharmacokinetic parameters selected from a Cmax less than about 13, pg/ml, or a Cmax less than about 7 pg/ml or an AUC less than about 40 pg hr/ml. These pharmacokinetic parameters are based on those reported to the European Medicines Agency for Thelin.
  • the pharmaceutical composition is selected from a semi-solid composition, such as a gel, ointment, lotion, emulsion, cream, paste, or jelly.
  • a semi-solid composition such as a gel, ointment, lotion, emulsion, cream, paste, or jelly.
  • a particularly useful example is a gel composition.
  • These semi-solid gel compositions have particularly useful physical and delivery characteristics.
  • compositions of the present invention comprise a pharmaceutically acceptable carrier.
  • the carrier can comprise a combination of excipient ingredients such as a C3-6 polyol, glycerol, an N-vinylpyrrolidone polymer, an antioxidant, a chelating agent, and water.
  • compositions of the present invention comprise a humectant.
  • the humectant is selected from the group consisting of a C3-C6 polyol, wherein the C3-C6 polyol is not intended to include glycerol, which when present the glycerol is contemplated as a separate ingredient.
  • the C3-C6 polyol is selected from the group consisting of 1 ,2-propylene glycol, 1 ,3 propylene glycol, 1 ,2-butylene glycol, 1 ,4- butylene glycol, 1 ,2-hexylene glycol, mannitol, sorbitol, xylitol, and combinations thereof.
  • the humectant can comprise from about 5% (w/w) to about 25% (w/w), or from about 7.5% (w/w) to about 22.5% (w/w), or from about 10% (w/w) to about 20% (w/w), or about 15% (w/w), or about 14.89% (w/w) of the composition.
  • the C3-6 diol, particularly if it is 1 ,2-propylene glycol can be used to q.s. the composition to 100% (w/w).
  • Q.S. or “q.s.” is an abbreviation for quantum satis, a Latin term meaning the amount which is enough, and has its origins as a quantity specification in medicine and pharmacology, where a similar term “quantum sufficd' (as much as is sufficient) has been used and similarly abbreviated.
  • compositions in certain embodiments comprise glycerol, as described immediately below.
  • glycerol is not considered part of the humectant definition, and when glycerol is present the compositions comprise a humectant component as described above.
  • compositions of the present invention comprise glycerol.
  • the glycerol can comprise from about 50% (w/w) to about 80% (w/w), or from about 55% (w/w) to about 75% (w/w), or from about 60% (w/w) to about 70% (w/w), or about 64% (w/w) of the composition.
  • compositions of the present invention comprise an N-vinylpyrrolidone polymer.
  • the N-vinylpyrrolidone polymer is also known as polyvinylpyrrolidone (PVP), and is also commonly called polyvidone or povidone.
  • the material is a water-soluble polymer made from the monomer N-vinylpyrrolidone.
  • the N-vinylpyrrolidone monomer of the polymer has the following chemical structure.
  • N-vinylpyrrolidone polymers are available in a range of molecular weights and related viscosity ranges, and can be selected according to the desired application properties. Although both homopolymers of the N-vinylpyrrolidone and copolymers with other monomers can be made, the homopolymers are particularly useful in the present invention.
  • the homopolymers are characterized by their molecular weights and the number of repeating monomer units, and are described by a “K” value, examples of which are povidone K30 and povidone K90.
  • the polymers generally have a molecular weight ranging from about 10,000 to about 700,000. Particularly useful in the present invention is povidone K30, which has the CAS registry number, 9003-39-8, and which has a molecular weight of about 40,000.
  • the N-vinylpyrrolidone polymer such as Povidone K30, can comprise from about 5% (w/w) to about 25% (w/w), or from about 7.5% (w/w) to about 22.5% (w/w), or from about 10% (w/w) to about 20% (w/w), or about 15% (w/w) of the composition.
  • compositions of the present invention comprise an antioxidant.
  • the antioxidant can be selected from the group consisting of acetone sodium bisulfite, alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid monohydrate, dodecyl gallate, erythorbic acid, fumaric acid, malic acid, mannitol, sorbitol, monothioglycerol, octyl gallate, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, thymol, vitamin E polyethylene glycol succinate, and N-acetylcysteine, or a combination thereof.
  • These components can be employed and used at levels appropriate for the formulation based on the knowledge of one with ordinary skill in the pharmaceutical
  • antioxidant useful herein is ascorbic acid.
  • the antioxidant such as ascorbic acid
  • compositions of the present invention comprise a chelating agent.
  • chelating agents useful herein include ethylenediaminetetraacetic acid (EDTA), citric acid, tartaric acid, triethanolamine, and combinations thereof.
  • EDTA ethylenediaminetetraacetic acid
  • a particularly useful chelating agent useful herein is ethylenediaminetetraacetic acid (EDTA).
  • the chelating agent such as ethylenediaminetetraacetic acid (EDTA) can comprise from about 0.001 % (w/w) to about 0.1 % (w/w), or from about 0.005% (w/w) to about 0.05% (w/w), or from about 0.0075% (w/w) to about 0.02% (w/w), or about 0.01 % (w/w) of the composition.
  • EDTA ethylenediaminetetraacetic acid
  • compositions of the present invention in some embodiments, such as solutions and gels comprise water. In other embodiments, such as the ointments, the compositions are substantially free of water.
  • the water when present in the solution and gel compositions, can comprise from about 1 % (w/w) to about 10% (w/w), or from about 2% (w/w) to about 7.5% (w/w), or from about 4% (w/w) to about 6% (w/w), or about 5% (w/w) of the composition.
  • compositions of the present invention can comprise one or more further ingredients selected from a preservative, an emulsifier, a surfactant or wetting agent, an emollient, a filmforming agent, a buffer or pH modifying agent, or a viscosity modifying agent.
  • a preservative an emulsifier, a surfactant or wetting agent, an emollient, a filmforming agent, a buffer or pH modifying agent, or a viscosity modifying agent.
  • the semi-solid pharmaceutical composition is in the form selected from the group consisting of a gel, ointment, lotion, emulsion, cream, jelly, or paste.
  • a gel, ointment, lotion, emulsion, cream, jelly, or paste can be employed and used at levels appropriate for the formulation based on the knowledge of one with ordinary skill in the pharmaceutical and formulation arts.
  • Methods of preparing the sitaxentan compositions are also intended as part of the present invention and would be apparent to one of ordinary skill in the pharmaceutical and formulation arts using standard formulation and mixing techniques.
  • the semi-solid compositions of the present invention can be prepared using standard mixing equipment and techniques.
  • An exemplary preparation method is as follows:
  • Sitaxentan sodium gels and solutions were prepared using the following steps:
  • the present invention utilizes a therapeutically effective amount of sitaxentan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for providing local or topical compositions for treating conditions such as cutaneous fibrosis and connective tissue diseases.
  • Such conditions can include scleroderma (including, but not limited to, systemic sclerosis and localized scleroderma), Raynaud’s phenomenon, Peyronie’s disease, sclerodactyly, cutaneous ulcers, morphea, en coup de sabre, cicatricial alopecia, scarring alopecia (including, but not limited to, lichen planopilaris, lichen planus, frontal fibrosing alopecia, central centrifugal cicatricial alopecia, folliculitis decalvens, discoid lupus erythematous, and dissecting cellulitis), rheumatoid arthritis, lupus, lichen sclerosis, keloid scar
  • the methods comprise locally or topically applying a therapeutically effective amount of sitaxentan, or a pharmaceutically acceptable salt thereof, to the mammal, such as a human patient, in need thereof.
  • a therapeutically effective amount of sitaxentan, or a pharmaceutically acceptable salt thereof to the mammal, such as a human patient, in need thereof.
  • the composition is applied to the skin of said human.
  • a unit dosage of the composition as described herein can be applied at least once daily.
  • a unit dosage of the composition can be applied at least twice daily, or at least three times daily, or at least four times daily, or at least once weekly, or at least twice weekly.
  • the composition can be applied ad libitum (i.e. as needed) or as prescribed by a physician or other healthcare professional.
  • Local or topical administration of the composition can be continued in the judgment of the physician or healthcare professional until the desired therapeutic benefit is achieved, i.e. until the cutaneous fibrosis or the connective tissue disease, such as scleroderma is treated. In some instances, it can be desirable to continue long term or chronic therapy. In other instances, it can be desirable to provide prophylactic or preventive treatment, particularly in individuals who have previously had the disease or are otherwise at risk of or susceptible to developing the disease.
  • Example 1 Effect of Sitaxentan on TGF-B1 Induced Fibroblasts in Male Cells
  • Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-gamma.
  • LLCT FC0024 lot 03869_male fibroblast, 23 year old Male normal human dermal fibroblast cells (LLCT FC0024 lot 03869_male fibroblast, 23 year old) were seeded to confluence in 96 well plates in 10% fetal bovine serum (FBS) Dulbecco’s modified eagle medium (DMEM).
  • FBS fetal bovine serum
  • DMEM modified eagle medium
  • the cells were washed to remove the FBS, and serum free media was added for 16 hr overnight (O/N).
  • the samples were optionally stained with CellTracker Green (5 uM) to produce fluorescence time zero images.
  • the cells were treated with increasing concentrations (1 pM, 3 pM, 10 pM, 30 pM, and 100 pM) of vehicle control, sitaxentan, and bosentan (as a comparator compound), in the presence of 50 ng/mL TGF-pi to induce fibrogenesis. Six replicate samples were run for each concentration.
  • the samples were incubated for 30 minutes. Images were taken and the distance of the scratch/ablation recorded.
  • VC vehicle control
  • SIT sitaxentan
  • BOS bosentan
  • Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-gamma.
  • LLCT FC0024 lot 00703_female fibroblast 45 year old
  • FBS fetal bovine serum
  • DMEM modified eagle medium
  • the cells were washed to remove the FBS, and serum free media was added for 16 hr overnight (O/N).
  • the samples were optionally stained with CellTracker Green (5 uM) to produce fluorescence time zero images.
  • the cells were treated with increasing concentrations (3 pM, 10 pM, 30 pM, and 100 pM) of vehicle control, sitaxentan, and bosentan (as a comparator compound), in the presence of 50 ng/mL TGF-[31 to induce fibrogenesis. Three replicate samples were run for each concentration.
  • the samples were incubated for 30 minutes.
  • VC vehicle control
  • SIT sitaxentan
  • BOS bosentan
  • sitaxentan The effect of sitaxentan on collagen production was measured in an AlphaLISA assay using male normal human dermal fibroblasts induced with TGF-[31 into a profibrotic phenotype. For this assay cells were grown for 48 hours in the presence of vehicle control, sitaxentan, and bosentan. See, http://www.perkinelmer.com/product/alphalisa-hpip-collagen-kit-100pts-al353hv.
  • An AlphaLISA assay was used, which is a variation of FRET (Fluorescence resonance energy transfer) technology that allows for the detection of molecules of interest in a no-wash, highly sensitive, quantitative assay.
  • FRET Fluorescence resonance energy transfer
  • a biotinylated anti-analyte antibody binds to Streptavidin-coated donor beads while another anti-analyte antibody is conjugated to AlphaLISA Acceptor beads.
  • the beads come into close proximity.
  • the excitation of the donor beads cause the release of singlet oxygen molecules that trigger a cascade of energy transfer in the acceptor beads, resulting in a sharp peak of light emission at 615 nm.
  • LLCT FC0024 lot 03869_male fibroblast, 23 year old Male normal human dermal fibroblast cells (LLCT FC0024 lot 03869_male fibroblast, 23 year old) were seeded to confluence in 96 well plates in 10% fetal bovine serum (FBS) Dulbecco’s modified eagle medium (DMEM).
  • FBS fetal bovine serum
  • DMEM modified eagle medium
  • the cells were washed to remove the FBS, and serum free media was added overnight (O/N).
  • the cells were then stimulated with 50 ng/mL TGF-[31 and treated.
  • the supernatant media above the cells in the wells was collected and diluted 1 :20 in serum-free DMEM media.
  • the plate was incubated 30 minutes at 23°C.
  • the plate was incubated 60 minutes at 23°C.
  • the plate was incubated 30 minutes at 23°C in the dark.
  • the plate was read using a Perkin Elmer EnVision-Alpha Reader (615 nm).
  • VC vehicle control
  • SIT sitaxentan
  • BOS bosentan
  • VC-NT vehicle control with no TGF- [31 treatment
  • the data for the 100 pM concentrations of vehicle control, sitaxentan, and bosentan are presented as bar graphs with statistical analyses in FIG. 3.
  • sitaxentan The effect of sitaxentan on cell viability, cell cytotoxicity, and apoptosis was measured in an assay using male normal human dermal fibroblasts induced with TGF- (31 into a profibrotic phenotype. For these assays cells were grown for 48 hours in the presence of vehicle control, sitaxentan, and bosentan. The appropriate assay reagents and measuring techniques were used as indicated herein.
  • LLCT FC0024 lot 03869_male fibroblast, 23 year old Male normal human dermal fibroblast cells (LLCT FC0024 lot 03869_male fibroblast, 23 year old) were seeded to confluence in 96 well plates in 10% fetal bovine serum (FBS) Dulbecco’s modified eagle medium (DMEM).
  • FBS fetal bovine serum
  • DMEM modified eagle medium
  • the cells were washed to remove the FBS, and serum free media is added overnight (O/N).
  • the cells were then stimulated with 50 ng/mL TGF-[31 and treated for 48 hours.
  • a master mix of the viability/cytotoxicity reagent was made by combining 10 uL of each substrate (GF-AFC and bis-AAF-R110) to 2 mLs of Assay Buffer (Promega, Cat # G6320). 20p I of this viability/cytotoxicity reagent was then added to each well and briefly mixed. The plate was incubated for 30 minutes at 37 °C prior to measuring fluorescence at: 400Ex/505Em (Viability) and 485Ex/520Em (Cytotoxicity).
  • apoptosis assay 1 OOpI of Caspase-Gio® 3/7 Reagent (Promega, Cat # G6320), for the apoptosis assay, was subsequently added after the viability/cytotoxicity fluorescent reads and briefly mixed.
  • the plate was incubated for an additional 30 minutes at room temperature prior to the measurement of luminescence to detect apoptosis.
  • Example 5 Preparation of a Composition for Topical Delivery
  • Sitaxentan sodium gels and solutions were prepared using the following steps:
  • compositions for gels and solutions are shown in the following Table 5.
  • compositions for ointments are shown in Tables 6 and 6.1 .
  • IVPT In vitro permeation testing
  • the 2% solution delivered the most API over 24hours followed by the 1 % solution.
  • the gels and ointments were mostly comparable in the amount of API delivery of the course of this study.
  • the gels appeared to be more efficient for drug release: they were able to deliver their maximum dose in ⁇ 4-8 hours, whereas the ointments and solutions continued releasing over 24 hours.
  • IVPT In vitro permeation testing
  • Example 8 In Vitro Permeation Testing
  • IVPT In vitro permeation testing
  • compositions and methods of the present invention where the term comprises is used with respect to the recited components of the compositions or steps of the methods, it is also contemplated that the compositions and methods consist essentially of, or consist of, the recited steps or components. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
  • composition can be described as being composed of the components prior to mixing, because upon mixing certain components can further react or be transformed into additional materials.

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Abstract

La présente invention concerne des compositions destinés à l'administration locale d'agents actifs médicamenteux. Ces compositions sont particulièrement utiles pour l'administration dermique ciblée d'antagonistes sélectifs du récepteur de l'endothéline-A (ETA), tels que le sitaxentan.
PCT/US2023/035194 2022-11-23 2023-10-16 Compositions pour l'administration locale de principes actifs médicamenteux WO2024112391A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050043402A1 (en) * 1996-11-14 2005-02-24 Halldor Thormar Methods and formulations for counteracting infection of mucosa or skin
US20170035727A1 (en) * 2014-04-28 2017-02-09 Epipharm Ag Treatment or prevention of seborrheic keratosis using artemisinin and derivatives thereof
WO2019173215A1 (fr) * 2018-03-07 2019-09-12 Timber Pharmaceuticals Llc Compositions et méthodes destinées au traitement de la fibrose kystique
WO2021134194A1 (fr) * 2019-12-30 2021-07-08 L'oreal Composition anhydre pour le soin des matières kératiniques
US20220241250A1 (en) * 2018-07-26 2022-08-04 Maruho Co., Ltd. Liquid topical preparation
US20220265546A1 (en) * 2020-01-10 2022-08-25 Briori Biotech, Llc Topical compositions containing rofecoxib and methods of making and using the same

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050043402A1 (en) * 1996-11-14 2005-02-24 Halldor Thormar Methods and formulations for counteracting infection of mucosa or skin
US20170035727A1 (en) * 2014-04-28 2017-02-09 Epipharm Ag Treatment or prevention of seborrheic keratosis using artemisinin and derivatives thereof
WO2019173215A1 (fr) * 2018-03-07 2019-09-12 Timber Pharmaceuticals Llc Compositions et méthodes destinées au traitement de la fibrose kystique
US20210038570A1 (en) * 2018-03-07 2021-02-11 Timber Pharmaceuticals, Inc. Compositions and methods for treating cutaneous fibrosis
US20220241250A1 (en) * 2018-07-26 2022-08-04 Maruho Co., Ltd. Liquid topical preparation
WO2021134194A1 (fr) * 2019-12-30 2021-07-08 L'oreal Composition anhydre pour le soin des matières kératiniques
US20220265546A1 (en) * 2020-01-10 2022-08-25 Briori Biotech, Llc Topical compositions containing rofecoxib and methods of making and using the same

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